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Acute Cardiac Impairment Associated With Concurrent Chemoradiotherapy for Esophageal Cancer: Magnetic Resonance Evaluation
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Gastrointestinal Cancer
Acute Cardiac Impairment Associated With Concurrent Chemoradiotherapy for Esophageal Cancer: Magnetic Resonance Evaluation Masamitsu Hatakenaka, M.D., Ph.D.,*,{ Masato Yonezawa, M.D.,* Takeshi Nonoshita, M.D.,* Katsumasa Nakamura, M.D., Ph.D.,* Hidetake Yabuuchi, M.D., Ph.D.,y Yoshiyuki Shioyama, M.D., Ph.D.,* Michinobu Nagao, M.D., Ph.D.,z Yoshio Matsuo, M.D., Ph.D.,* Takeshi Kamitani, M.D.,* Taiki Higo, M.D.,x Kei Nishikawa, R.T.,k Taro Setoguchi, M.D.,** and Hiroshi Honda, M.D., Ph.D.* Departments of *Clinical Radiology, yHealth Sciences, zMolecular Imaging and Diagnostic Radiology, and xCardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; {Department of Diagnostic Radiology, School of Medicine, Sapporo Medical University, Sapporo, Japan; kRadiology Center, Kyushu University Hospital, Kyushu University, Fukuoka, Japan; and **Department of Radiology, National Hospital Organization, Kokura Medical Center, Fukuoka, Japan Received Sep 8, 2011, and in revised form Nov 16, 2011. Accepted for publication Nov 30, 2011
Summary Left ventricle (LV) function of 31 esophageal cancer patients received concurrent chemoradiotherapy (CCRT) was evaluated using magnetic resonance imaging. Patients were classified into two groups regarding mean LV dose. In low LV-dose group, LV ejection fraction decreased significantly. In high LV-dose group, LV end-diastolic volume index, stroke volume index, ejection fraction, and wall motion in segments 8e10
Purpose: To evaluate acute cardiac effects of concurrent chemoradiotherapy (CCRT) for esophageal cancer. Methods and Materials: This prospective study was approved by the institutional review board, and written informed consent was obtained from all participants. The left ventricular function (LVF) of 31 patients with esophageal cancer who received cisplatin and 5-fluorouracilebased CCRT was evaluated using cardiac cine magnetic resonance imaging. The patients were classified into two groups according to mean LV dose. The parameters related to LVF were compared between before and during (40 Gy) or between before and after CCRT using a Wilcoxon matched-pairs single rank test, and parameter ratios (during/before CCRT, after/before CCRT) were also compared between the groups with a t test. Data were expressed as mean SE. Results: In the low LV-dose group (n Z 10; mean LV dose <0.6 Gy), LV ejection fraction decreased significantly (before vs. during vs. after CCRT; 62.7% 2.98% vs. 59.8% 2.56% vs. 60.6% 3.89%; p < 0.05). In the high LV-dose group (n Z 21; mean LV dose of 3.6e41.2 Gy), LV end-diastolic volume index (before vs. after CCRT; 69.1 2.93 vs. 57.0 3.23 mL/m2), LV stroke volume index (38.6 1.56 vs. 29.9 1.60 mL/m2), and LV ejection fraction (56.9% 1.79% vs. 52.8% 1.15%) decreased significantly (p < 0.05) after CCRT. Heart rate increased significantly (before vs. during vs. after CCRT; 66.8 3.05 vs. 72.4 4.04 vs. 85.4 3.75 beats per minute, p < 0.01). Left ventricle wall motion decreased significantly (p < 0.05) in segments 8 (before vs. during vs. after CCRT; 6.64 0.54 vs. 4.78 0.43
Reprint requests to: Masamitsu Hatakenaka, M.D., Ph.D., Sapporo Medical University, School of Medicine, Department of Diagnostic Radiology, Minami 1, Nishi 16, Chuo-ku, Sapporo City, Japan. Tel: (þ81) Int J Radiation Oncol Biol Phys, Vol. 83, No. 1, pp. e67ee73, 2012 0360-3016/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ijrobp.2011.12.018
11-611-2111, ext. 3501; Fax: (þ81) 11-633-6885; E-mail: mhatakenaka@ sapmed.ac.jp Conflict of interest: none.
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decreased significantly. Heart rate increased significantly. CCRT for esophageal cancer impairs LV function from an early treatment stage.
vs. 4.79 0.50 mm), 9 (6.88 0.45 vs. 5.04 0.38 vs. 5.27 0.47 mm), and 10 (9.22 0.48 vs. 8.08 0.34 vs. 8.19 0.56 mm). The parameter ratios of LV end-diastolic volume index, stroke volume index, wall motion in segment 9, and heart rate showed significant difference (p < 0.05) after CCRT between the groups. Conclusions: Concurrent chemoradiotherapy for esophageal cancer impairs LVF from an early treatment stage. This impairment is prominent in patients with high LV dose. Ó 2012 Elsevier Inc. Keywords: Esophageal cancer, Chemoradiotherapy, Cardiac function, Magnetic resonance imaging
Introduction Concerns about radiation-related cardiac toxicities have been increasing, especially in patients with breast cancer who receive adjuvant radiotherapy (1, 2). Because such patients are expected to have a relatively good prognosis, cardiac toxicities that may cause death are clinically important. It would be meaningless that the patients lose their lives because of cardiac complications although primary breast cancers are completely cured. Cisplatin and 5-fluorouracilebased concurrent chemoradiotherapy (CCRT) has become a standard treatment option for patients with unresectable or medically inoperable esophageal cancer. Although the survival rate for this treatment has not been satisfactory, it has been improving recently. Compared with breast cancer treatment, the radiation dose to the left ventricle (LV) in patients who receive CCRT for esophageal cancer is greater, and the extent of the LV receiving radiation is also larger. In this context, the importance of cardiac toxicities, including pericarditis, cardiovascular damage including cardiac infarction, and cardiomyopathy, has been increasing (3e6). Ultrasonography and cardiac scintigraphy have been considered suitable methods for evaluating cardiac function noninvasively; however, magnetic resonance (MR) imaging including cine MR imaging has been accepted as the most reliable method (7). To our knowledge, however, the cardiac effects of CCRT for esophageal cancer have not yet been evaluated using cine MR imaging. The purpose of this study was to evaluate the acute cardiac effects of CCRT for esophageal cancer by using cine MR imaging. Our hypothesis was that CCRT for esophageal cancer impairs left ventricular function (LVF) from an early treatment stage, and the impairment of LVF may be prominent in patients with mid- or lower thoracic esophageal cancer, in whom the LV dose is usually higher than in those with cervical or upper thoracic esophageal cancer.
Methods and Materials Patients and treatment This prospective study was approved by the institutional review board, and written informed consent was obtained from all patients. The 35 patients who were scheduled to receive CCRT for esophageal cancer in our department between November 2007 and June 2010 were consecutively enrolled in this study. Those who had a history of cardiovascular or neurovascular disease (1 case each of angina pectoris, aortic aneurysm, and cerebral infarct) and 1 patient who received radiotherapy alone because of renal dysfunction were
excluded. Thus a total of 31 patients (25 male and 6 female; 47e85 years of age; median age 66 years) were included in this study. The locations of the disease were as follows: 8 cervical, 3 upper thoracic, 15 mid-thoracic, and 5 lower thoracic. The stages of the disease according to International Union Against Cancer 1997 criteria were as follows: 4 Stage I, 7 Stage II, 18 Stage III, and 2 Stage IV. The histologic diagnoses were all squamous cell carcinomas, except for 1 case of lymphoepithelial carcinoma. Patient characteristics are summarized in Table 1. Radiotherapy was performed at a daily dose of 1.8e2.0 Gy, five times per week using a Varian 21EX linear accelerator (Varian Medical Systems, Palo Alto, CA). Radiotherapy was delivered through anteroposterior portals using 4-, 6-, or 10-MV photon beams with a T-shaped or I-shaped field including primary lesions and regional nodes to 40e41.4 Gy, and the boost was delivered through parallel opposed oblique portals avoiding the spinal cord. Twenty-five patients were treated by CCRT with a low-dose protocol (cisplatin 5 mg/m2 bolus infusion and 5-fluorouracil 300 mg/m2 24-h continuous infusion during radiotherapy), and the remaining 6 patients were treated with a standard-dose protocol (cisplatin 70 mg/m2 bolus infusion on Day 1, and 5-fluorouracil 700 mg/m2 24-h continuous infusion on Days 1e4; two cycles are given during radiotherapy). This study included two types of treatments: Type A included patients who received radical CCRT with a total radiation dose of 55.4e71 Gy (n Z 24, 18 patients treated with a low-dose chemotherapy protocol and 6 patients with a standard-dose one). (Total radiation dose of approximately 60 Gy with 30 fractions is a standard CCRT for advanced esophageal cancer in Japan.) Type B included patients who received a total radiation dose of 40e41.4 Gy and were treated by surgery after CCRT (n Z 7, all patients treated with a low-dose chemotherapy protocol). The treatment schema is shown in Fig. 1.
Patient classification according to LV dose The patients were divided into two groups according to their mean total LV dose: a low LV-dose and a high LV-dose group. The contour of LV was defined and the mean LV dose was calculated with an Eclipse planning system (Varian Medical Systems). This procedure was performed by a radiation oncologist (T.N.) with 12 years’ experience, who was blinded to the data of MR imaging. Representative dose distributions are shown in Fig. 2.
MR imaging Magnetic resonance examination was performed with a 1.5-T system (Gyroscan Intera Achieva; Philips Medical Systems, Best,
Volume 83 Number 1 2012 Table 1
CCRT for esophageal cancer impairs LVF
Patient characteristics according to LV dose Mean LV dose Parameter
Low
High
p
Age (y), mean SE 66.7 9.1 63.8 11.9 NS Gender Male 7 18 NS Female 3 3 Stage I 0 4 NS II 4 3 III 6 12 IV 0 2 Location Cervical 7 1 <0.01 Upper thoracic 3 0 Mid-thoracic 0 15 Lower thoracic 0 5 Cardiac risk factor Smoking (þ) 5 15 NS Smoking () 5 6 Hypertension (þ) 3 4 NS Hypertension () 7 17 Hypercholesterolemia (þ) 0 1 NS Hypercholesterolemia () 10 20 BMI (kg/m2), mean SE 21.1 2.8 19.5 2.4 NS Chemotherapy Low dose 8 17 NS Standard dose 2 4 Abbreviations: LV Z left ventricle; NS Z nonsignificant (p > 0.05); BMI Z body mass index.
The Netherlands), and a cardiac coil with five channels was used. The LVF was evaluated using cine MR imaging with 20 heart phases, a 350-mm field of view, 10-mm slice thickness, 0-mm slice gap, 192 184 matrix, 3.2-ms repetition time, 1.6-ms echo time, 55 flip angle, and balanced turbo field-echo sequence. The cine MR imaging was obtained before CCRT for all 31 patients, at a primary lesion dose of approximately 40 Gy for 27 patients, and after CCRT for 19 patients. The duration between the MR examination before CCRT and the start of CCRT was 0e11 days, and the median was 1 day. The duration between the MR examination after CCRT and the completion of CCRT was 0e12 days, and the median was 3 days. The exact radiation doses to the primary lesion at the MR examination performed at approximately
Fig. 1. Scheme of the treatments. CCRT Z concurrent chemoradiotherapy; MRI Z magnetic resonance imaging.
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40 Gy and after CCRT were distributed from 34.2 to 43.4 Gy (median, 41.4 Gy) and from 60.0 to 71.4 Gy (median, 65.4 Gy), respectively. (Some patients received MR examination either at approximately 40 Gy or after CCRT.)
Data acquisition and analysis Patient characteristics were compared as follows: age and body mass index were compared between low and high LV-dose groups using a t test, and other categoric data were compared using a c2 test. Probability (p) values of <0.05 were considered statistically significant. The LVF analysis was performed with View Forum (Philips Medical Systems) and by M.Y. and K.N. in consensus (M.Y. has 8 years of experience in cardiac imaging, and K.N. has 15 years of experience in MR imaging). Both were blinded to the CCRT method used for each patient. Several parameters related to LVF (end-diastolic volume index [LV-EDVI], end-systolic volume index [LVESVI], stroke volume index [LV-STVI], ejection fraction [LV-EF], cardiac output index [COI], heart rate [HR], and LV wall motion [LV-WM] and LV wall thickening [LV-WT] at the mid-LV portion [segments 7e12 according to the American Heart Association]) were measured and compared between before CCRT and at approximately 40 Gy or after CCRT using a Wilcoxon matchedpairs single rank test. The parameter ratios of LV-EF, LV-EDVI, LVESVI, LV-STVI, HR, COI, LV-WM, LV-WT, and body weight at approximately 40 Gy (i.e., the LV-EF, LV-EDVI, LV-ESVI, LVSTVI, HR, COI, LV-WM, LV-WT, and body weight at approximately 40 Gy divided by those before CCRT) and those after CCRT (LV-EF, LV-EDVI, LV-ESVI, LV-STVI, HR, COI, LV-WM, LV-WT, and body weight after CCRT divided by those before CCRT) were compared between the low and high LV-dose groups using a t test. A p value <0.05 was considered statistically significant. Data were expressed as the mean SE unless otherwise specified. To minimize the effects of height and body weight, LV-EDVI, LV-ESVI, LVSTVI, and COI (divided by body surface area) were used.
Results Patient classification according to LV dose The low LV-dose group included 10 patients and consisted of cervical and upper thoracic cancers. The mean LV dose was <0.6 Gy (mean, 0.37 Gy) at MR examination at approximately 40 Gy and <0.5 Gy (mean, 0.33 Gy) at MR examination after CCRT. The constitution of the patients undergoing cine MR imaging differed between the MR examinations at approximately 40 Gy and that after CCRT; therefore, the mean LV dose at MR examination at approximately 40 Gy was greater than that at MR examination after CCRT. The high LV-dose group included 21 patients and consisted of mid- and lower thoracic cancers, including 1 case of cervical cancer with extended lymph node metastasis. The mean LV dose was distributed from 3.6 to 29.4 Gy (mean, 15.5 Gy; median, 15.6 Gy) at MR examination at approximately 40 Gy and from 4.6 to 41.2 Gy (mean, 18.1 Gy; median, 16.3 Gy) at MR examination after CCRT. There were no significant differences with respect to age, gender, disease stage, cardiac risk factors, or chemotherapy method between patients receiving low and high LV doses, but the primary lesion location did differ significantly between the two dose groups. The
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Fig. 2. Representative dose distributions of cases in the low left ventricle (LV)-dose (a, b) and high LV-dose (c, d, e) group. Coronal (a) and axial (b) views of dose distribution in a case with cervical esophageal cancer. Left ventricle receives no direct radiation. Coronal (c), axial (d), and short LVaxis (e) views of dose distribution in a case with mid-thoracic esophageal cancer. A summation of the anteroposterior and parallel opposed oblique fields is shown. Numbers indicate the cardiac segments according to the American Heart Association classification (e). classification of patient characteristics according to LV dose is summarized in Table 1.
Comparison of parameters related to LVF between before CCRT and at approximately 40 Gy or after CCRT In the low LV-dose group, the LV-EF decreased significantly (p < 0.05) both at approximately 40 Gy (59.8% 2.56%) and after
CCRT (60.6% 3.89%) compared with before CCRT (62.7% 2.98%). No other parameters showed significant change. In the high LV-dose group, the LV-EF, LV-EDVI, and LV-STVI decreased significantly (p < 0.05) after CCRT compared with before CCRT. The HR increased significantly (p < 0.01) both at approximately 40 Gy and after CCRT compared with before CCRT. The LV-WM of segments 8, 9, and 10 decreased significantly (p < 0.05) both at approximately 40 Gy and after CCRT compared with before CCRT. No other parameters showed significant change. The data are summarized in Table 2.
Volume 83 Number 1 2012 Table 2
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Change of left ventricular function in the high LV-dose group MR examination Parameter
LV-EF (%) LV-EDVI (mL/m2) LV-STVI (mL/m2) HR (beats/min) LV-WM (mm) in segment 8 LV-WM (mm) in segment 9 LV-WM (mm) in segment 10
Before CCRT 56.9 69.1 38.6 66.8 6.64 6.88 9.22
1.79 2.93 1.56 3.05 0.54 0.45 0.48
40 Gy 55.0 64.7 35.2 72.4 4.78 5.04 8.08
1.42 2.49 1.11 4.04y 0.43y 0.38y 0.34*
After CCRT 52.8 57.0 29.9 85.4 4.79 5.27 8.19
1.15* 3.23y 1.60y 3.75y 0.50* 0.47y 0.56*
Abbreviations: LV Z left ventricle; MR Z magnetic resonance; CCRT Z concurrent chemoradiotherapy; EF Z ejection fraction; EDVI Z enddiastolic volume index; STVI Z stroke volume index; HR Z heart rate; WM Z wall motion. * p < 0.05 vs. before CCRT. y p < 0.01 vs. before CCRT.
Comparison of parameter ratios related to LVF between the low and high LV-dose groups Significant differences (p < 0.05) in the parameter ratios between the low and high LV-dose groups were observed only in the values calculated after CCRT for LV-EDVI ratio, LV-STVI ratio, HR ratio, and LV-WM ratio of segment 9. No other parameters, including LV-EF ratio and body weight ratio, showed significance either at approximately 40 Gy or after CCRT. The results are summarized in Fig. 3.
Discussion The results of this study indicate that LVF, both systolic and diastolic, is impaired from an early treatment stage in patients who received cisplatin and 5-fluorouracilebased CCRT for esophageal cancer. The cardiac toxicity of CCRT for esophageal cancer has been considered as one of the late toxicities (3, 8, 9); however, the results of this study reveal that parameters related to LVF decrease significantly immediately after CCRT compared with those before CCRT. To our knowledge, this is the first report to detect acute cardiac dysfunction, that is a reduction in LV-EF, LV-EDVI, LV-STVI, and LV-WM and an increase in HR, using cine MR imaging in patients who received CCRT for esophageal cancer. As for LV-EF, a significant reduction has also been reported in patients who received platinum-based chemoradiotherapy for esophageal cancer after treatment, according to multigated acquisition scanning (10, 11). Cisplatin and 5-fluorouracilebased chemotherapy impairs systolic LVF. Systolic dysfunction detected as a reduction in LV-EF was observed both in the low LV-dose and high LV-dose groups in the present study. This suggests that the decrease in LV-EF may happen irrespective of the LV radiation dose. The fact that the ratios of LV-EF after CCRT (i.e., the LV-EF after CCRT divided by the LV-EF before CCRT) showed no significant difference between the low and high LV-dose groups supports this interpretation (Fig. 3). The fact that 5-fluorouracil has been reported to induce ischemic syndrome, arrhythmia, and cardiomyopathy (12, 13) is not discrepant with our results. Late cardiovascular complications by cisplatin have also been reported (14). Platinum-based therapies are also known to increase the risk of thrombus formation (15e17).
Direct radiation to LV might impair diastolic LVF dominantly. In the high LV-dose group, the LV-EDVI and LV-STVI decreased significantly after CCRT (Table 2), and the LV-ESVI showed no significant change. Further, the impairment of LV-WM was detected both at approximately 40 Gy and after CCRT only at segments 8, 9, and 10 (Table 2), where the radiation dose is higher than at the other segments (Fig. 2). These results suggest that direct radiation to LV might predominantly impair diastolic function through a restriction of wall motion in the radiated areas. The result that a significant difference was observed in the ratio of LV-EDVI, LV-STVI, and LV-WM in segment 9 after CCRT between the low and high LV-dose groups supports this interpretation (Fig. 3). The fact that the ratio of LV-EF after CCRT showed no significant difference between the low and high LV-dose groups also supports this interpretation (Fig. 3). Radiation-induced direct myocardial damage, that is, a significant elevation in troponin I and brain natriuretic peptide during radiotherapy for lung and breast cancer, has been reported (18). In the present study, T2weighted images with fat saturation were obtained in some cases as to detect edematous or fibrotic change of LV; however, no signal increase or decrease in the irradiated areas compared with the nonirradiated areas was observed visually (data not shown). We suspected that a difference in the degree of dehydration related to CCRT between the low and high LV-dose groups may have affected the results, with respect to the decrease in LV-EDVI and increase in HR, and we therefore compared the ratio of body weight between these two groups. However, no significant difference was observed. We consider that a difference in the degree of dehydration related to CCRT does not affect the results. Late diastolic dysfunction and its association with stress-induced ischemia and a worse prognosis have been reported in patients who received mediastinal radiation of >35 Gy for Hodgkin’s disease (19). On the other hand, in breast cancer, systolic LV dysfunction, a regional strain and strain rate reductions, immediately after adjuvant radiotherapy has been reported in a study assessing LVF using cardiac ultrasonography (20). The difference in the extent and location of LV that receive radiation may contribute to the difference in results between breast and esophageal cancer. The LV area included in the radiation field is usually restricted to the apex in only left-sided breast cancer. We also consider that the lack of change in COI in the high LV-dose group either at approximately 40 Gy or after CCRT was probably due to a compensation for the decrease in LV-STVI by the elevation of HR. The fact that LV-STVI and HR showed the opposite
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Fig. 3. Comparison of parameter ratios (after concurrent chemoradiotherapy [CCRT]/before CCRT) between low left ventricle (LV)-dose and high LV-dose groups. Left ventricle ejection fraction (LV-EF) ratio (a), LV end-diastolic volume index (LV-EDVI) ratio (b), LV stroke volume index (LV-STVI) ratio (c), heart rate (HR) ratio (d), and LV wall motion (LV-WM) ratio of segment 9 (e) are shown. directional changes after CCRT supports this interpretation (Table 2 and Fig. 3). The results of this study are limited in that the total number of patients is small. A more comprehensive study with a larger number of patients and detailed evaluation on cardiac function, including diastolic LVF, will be needed to reach a definitive conclusion. Further, a study with longer observation time may also be needed to determine whether the acute cardiac impairment observed in this study continues to correlate with late cardiac toxicities. In conclusion, cisplatin and 5-fluorouracilebased CCRT for esophageal cancer impairs LVF from an early treatment stage, and this impairment is prominent in the high LV-dose group.
References 1. Evans ES, Prosnitz RG, Yu X, et al. Impact of patient-specific factors, irradiated left ventricular volume, and treatment set-up errors on the development of myocardial perfusion defects after radiation therapy for left-sided breast cancer. Int J Radiat Oncol Biol Phys 2006;66: 1125e1134. 2. Borger JH, Hooning MJ, Boersma LJ, et al. Cardiotoxic effects of tangential breast irradiation in early breast cancer patients: The role of
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irradiated heart volume. Int J Radiat Oncol Biol Phys 2007;69: 1131e1138. Ishikura S, Nihei K, Ohtsu A, et al. Long-term toxicity after definitive chemoradiotherapy for squamous cell carcinoma of the thoracic esophagus. J Clin Oncol 2003;21:2697e2702. Schultz-Hector S, Trott KR. Radiation-induced cardiovascular diseases: Is the epidemiologic evidence compatible with the radiobiologic data? Int J Radiat Oncol Biol Phys 2007;67:10e18. Gagliardi G, Constine LS, Moiseenko V, et al. Radiation dose-volume effects in the heart. Int J Radiat Oncol Biol Phys 2010;76:S77eS85. Darby SC, Cutter DJ, Boerma M, et al. Radiation-related heart disease: Current knowledge and future prospects. Int J Radiat Oncol Biol Phys 2010;76:656e665. Masci PG, Dymarkowski S, Rademakers FE, et al. Determination of regional ejection fraction in patients with myocardial infarction by using merged late gadolinium enhancement and cine MR: Feasibility study. Radiology 2009;250:50e60. Kumekawa Y, Kaneko K, Ito H, et al. Late toxicity in complete response cases after definitive chemoradiotherapy for esophageal squamous cell carcinoma. J Gastroenterol 2006;41:425e432. Morota M, Gomi K, Kozuka T, et al. Late toxicity after definitive concurrent chemoradiotherapy for thoracic esophageal carcinoma. Int J Radiat Oncol Biol Phys 2009;75:122e128. Mukherjee S, Aston D, Minett M, et al. The significance of cardiac doses received during chemoradiation of oesophageal and gastrooesophageal junctional cancers. Clin Oncol (R Coll Radiol) 2003; 15:115e120.
Volume 83 Number 1 2012 11. Tripp P, Malhotra HK, Javle M, et al. Cardiac function after chemoradiation for esophageal cancer: Comparison of heart dose-volume histogram parameters to multiple gated acquisition scan changes. Dis Esophagus 2005;18:400e405. 12. Frickhofen N, Beck FJ, Jung B, et al. Capecitabine can induce acute coronary syndrome similar to 5-fluorouracil. Ann Oncol 2002;13:797e801. 13. Kosmas C, Kallistratos MS, Kopterides P, et al. Cardiotoxicity of fluoropyrimidines in different schedules of administration: A prospective study. J Cancer Res Clin Oncol 2008;134:75e82. 14. Meinardi MT, Gietema JA, van der Graaf WT, et al. Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol 2000;18:1725e1732. 15. Weijl NI, Rutten MF, Zwinderman AH, et al. Thromboembolic events during chemotherapy for germ cell cancer: A cohort study and review of the literature. J Clin Oncol 2000;18:2169e2178.
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16. Feldman DR, Bosl GJ, Sheinfeld J, et al. Medical treatment of advanced testicular cancer. JAMA 2008;299:672e684. 17. Torrisi JM, Schwartz LH, Gollub MJ, et al. CT findings of chemotherapy-induced toxicity: What radiologists need to know about the clinical and radiologic manifestations of chemotherapy toxicity. Radiology 2011;258:41e56. 18. Nellessen U, Zingel M, Hecker H, et al. Effects of radiation therapy on myocardial cell integrity and pump function: Which role for cardiac biomarkers? Chemotherapy 2010;56:147e152. 19. Heidenreich PA, Hancock SL, Vagelos RH, et al. Diastolic dysfunction after mediastinal irradiation. Am Heart J 2005;150: 977e982. 20. Erven K, Jurcut R, Weltens C, et al. Acute radiation effects on cardiac function detected by strain rate imaging in breast cancer patients. Int J Radiat Oncol Biol Phys 2011;79:1444e1451.
Radiation Oncology biology
physics
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Clinical Investigation: Gastrointestinal Cancer
Acute Cardiac Impairment Associated With Concurrent Chemoradiotherapy for Esophageal Cancer: Magnetic Resonance Evaluation Masamitsu Hatakenaka, M.D., Ph.D.,*,{ Masato Yonezawa, M.D.,* Takeshi Nonoshita, M.D.,* Katsumasa Nakamura, M.D., Ph.D.,* Hidetake Yabuuchi, M.D., Ph.D.,y Yoshiyuki Shioyama, M.D., Ph.D.,* Michinobu Nagao, M.D., Ph.D.,z Yoshio Matsuo, M.D., Ph.D.,* Takeshi Kamitani, M.D.,* Taiki Higo, M.D.,x Kei Nishikawa, R.T.,k Taro Setoguchi, M.D.,** and Hiroshi Honda, M.D., Ph.D.* Departments of *Clinical Radiology, yHealth Sciences, zMolecular Imaging and Diagnostic Radiology, and xCardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; {Department of Diagnostic Radiology, School of Medicine, Sapporo Medical University, Sapporo, Japan; kRadiology Center, Kyushu University Hospital, Kyushu University, Fukuoka, Japan; and **Department of Radiology, National Hospital Organization, Kokura Medical Center, Fukuoka, Japan Received Sep 8, 2011, and in revised form Nov 16, 2011. Accepted for publication Nov 30, 2011
Summary Left ventricle (LV) function of 31 esophageal cancer patients received concurrent chemoradiotherapy (CCRT) was evaluated using magnetic resonance imaging. Patients were classified into two groups regarding mean LV dose. In low LV-dose group, LV ejection fraction decreased significantly. In high LV-dose group, LV end-diastolic volume index, stroke volume index, ejection fraction, and wall motion in segments 8e10
Purpose: To evaluate acute cardiac effects of concurrent chemoradiotherapy (CCRT) for esophageal cancer. Methods and Materials: This prospective study was approved by the institutional review board, and written informed consent was obtained from all participants. The left ventricular function (LVF) of 31 patients with esophageal cancer who received cisplatin and 5-fluorouracilebased CCRT was evaluated using cardiac cine magnetic resonance imaging. The patients were classified into two groups according to mean LV dose. The parameters related to LVF were compared between before and during (40 Gy) or between before and after CCRT using a Wilcoxon matched-pairs single rank test, and parameter ratios (during/before CCRT, after/before CCRT) were also compared between the groups with a t test. Data were expressed as mean SE. Results: In the low LV-dose group (n Z 10; mean LV dose <0.6 Gy), LV ejection fraction decreased significantly (before vs. during vs. after CCRT; 62.7% 2.98% vs. 59.8% 2.56% vs. 60.6% 3.89%; p < 0.05). In the high LV-dose group (n Z 21; mean LV dose of 3.6e41.2 Gy), LV end-diastolic volume index (before vs. after CCRT; 69.1 2.93 vs. 57.0 3.23 mL/m2), LV stroke volume index (38.6 1.56 vs. 29.9 1.60 mL/m2), and LV ejection fraction (56.9% 1.79% vs. 52.8% 1.15%) decreased significantly (p < 0.05) after CCRT. Heart rate increased significantly (before vs. during vs. after CCRT; 66.8 3.05 vs. 72.4 4.04 vs. 85.4 3.75 beats per minute, p < 0.01). Left ventricle wall motion decreased significantly (p < 0.05) in segments 8 (before vs. during vs. after CCRT; 6.64 0.54 vs. 4.78 0.43
Reprint requests to: Masamitsu Hatakenaka, M.D., Ph.D., Sapporo Medical University, School of Medicine, Department of Diagnostic Radiology, Minami 1, Nishi 16, Chuo-ku, Sapporo City, Japan. Tel: (þ81) Int J Radiation Oncol Biol Phys, Vol. 83, No. 1, pp. e67ee73, 2012 0360-3016/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ijrobp.2011.12.018
11-611-2111, ext. 3501; Fax: (þ81) 11-633-6885; E-mail: mhatakenaka@ sapmed.ac.jp Conflict of interest: none.
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decreased significantly. Heart rate increased significantly. CCRT for esophageal cancer impairs LV function from an early treatment stage.
vs. 4.79 0.50 mm), 9 (6.88 0.45 vs. 5.04 0.38 vs. 5.27 0.47 mm), and 10 (9.22 0.48 vs. 8.08 0.34 vs. 8.19 0.56 mm). The parameter ratios of LV end-diastolic volume index, stroke volume index, wall motion in segment 9, and heart rate showed significant difference (p < 0.05) after CCRT between the groups. Conclusions: Concurrent chemoradiotherapy for esophageal cancer impairs LVF from an early treatment stage. This impairment is prominent in patients with high LV dose. Ó 2012 Elsevier Inc. Keywords: Esophageal cancer, Chemoradiotherapy, Cardiac function, Magnetic resonance imaging
Introduction Concerns about radiation-related cardiac toxicities have been increasing, especially in patients with breast cancer who receive adjuvant radiotherapy (1, 2). Because such patients are expected to have a relatively good prognosis, cardiac toxicities that may cause death are clinically important. It would be meaningless that the patients lose their lives because of cardiac complications although primary breast cancers are completely cured. Cisplatin and 5-fluorouracilebased concurrent chemoradiotherapy (CCRT) has become a standard treatment option for patients with unresectable or medically inoperable esophageal cancer. Although the survival rate for this treatment has not been satisfactory, it has been improving recently. Compared with breast cancer treatment, the radiation dose to the left ventricle (LV) in patients who receive CCRT for esophageal cancer is greater, and the extent of the LV receiving radiation is also larger. In this context, the importance of cardiac toxicities, including pericarditis, cardiovascular damage including cardiac infarction, and cardiomyopathy, has been increasing (3e6). Ultrasonography and cardiac scintigraphy have been considered suitable methods for evaluating cardiac function noninvasively; however, magnetic resonance (MR) imaging including cine MR imaging has been accepted as the most reliable method (7). To our knowledge, however, the cardiac effects of CCRT for esophageal cancer have not yet been evaluated using cine MR imaging. The purpose of this study was to evaluate the acute cardiac effects of CCRT for esophageal cancer by using cine MR imaging. Our hypothesis was that CCRT for esophageal cancer impairs left ventricular function (LVF) from an early treatment stage, and the impairment of LVF may be prominent in patients with mid- or lower thoracic esophageal cancer, in whom the LV dose is usually higher than in those with cervical or upper thoracic esophageal cancer.
Methods and Materials Patients and treatment This prospective study was approved by the institutional review board, and written informed consent was obtained from all patients. The 35 patients who were scheduled to receive CCRT for esophageal cancer in our department between November 2007 and June 2010 were consecutively enrolled in this study. Those who had a history of cardiovascular or neurovascular disease (1 case each of angina pectoris, aortic aneurysm, and cerebral infarct) and 1 patient who received radiotherapy alone because of renal dysfunction were
excluded. Thus a total of 31 patients (25 male and 6 female; 47e85 years of age; median age 66 years) were included in this study. The locations of the disease were as follows: 8 cervical, 3 upper thoracic, 15 mid-thoracic, and 5 lower thoracic. The stages of the disease according to International Union Against Cancer 1997 criteria were as follows: 4 Stage I, 7 Stage II, 18 Stage III, and 2 Stage IV. The histologic diagnoses were all squamous cell carcinomas, except for 1 case of lymphoepithelial carcinoma. Patient characteristics are summarized in Table 1. Radiotherapy was performed at a daily dose of 1.8e2.0 Gy, five times per week using a Varian 21EX linear accelerator (Varian Medical Systems, Palo Alto, CA). Radiotherapy was delivered through anteroposterior portals using 4-, 6-, or 10-MV photon beams with a T-shaped or I-shaped field including primary lesions and regional nodes to 40e41.4 Gy, and the boost was delivered through parallel opposed oblique portals avoiding the spinal cord. Twenty-five patients were treated by CCRT with a low-dose protocol (cisplatin 5 mg/m2 bolus infusion and 5-fluorouracil 300 mg/m2 24-h continuous infusion during radiotherapy), and the remaining 6 patients were treated with a standard-dose protocol (cisplatin 70 mg/m2 bolus infusion on Day 1, and 5-fluorouracil 700 mg/m2 24-h continuous infusion on Days 1e4; two cycles are given during radiotherapy). This study included two types of treatments: Type A included patients who received radical CCRT with a total radiation dose of 55.4e71 Gy (n Z 24, 18 patients treated with a low-dose chemotherapy protocol and 6 patients with a standard-dose one). (Total radiation dose of approximately 60 Gy with 30 fractions is a standard CCRT for advanced esophageal cancer in Japan.) Type B included patients who received a total radiation dose of 40e41.4 Gy and were treated by surgery after CCRT (n Z 7, all patients treated with a low-dose chemotherapy protocol). The treatment schema is shown in Fig. 1.
Patient classification according to LV dose The patients were divided into two groups according to their mean total LV dose: a low LV-dose and a high LV-dose group. The contour of LV was defined and the mean LV dose was calculated with an Eclipse planning system (Varian Medical Systems). This procedure was performed by a radiation oncologist (T.N.) with 12 years’ experience, who was blinded to the data of MR imaging. Representative dose distributions are shown in Fig. 2.
MR imaging Magnetic resonance examination was performed with a 1.5-T system (Gyroscan Intera Achieva; Philips Medical Systems, Best,
Volume 83 Number 1 2012 Table 1
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Patient characteristics according to LV dose Mean LV dose Parameter
Low
High
p
Age (y), mean SE 66.7 9.1 63.8 11.9 NS Gender Male 7 18 NS Female 3 3 Stage I 0 4 NS II 4 3 III 6 12 IV 0 2 Location Cervical 7 1 <0.01 Upper thoracic 3 0 Mid-thoracic 0 15 Lower thoracic 0 5 Cardiac risk factor Smoking (þ) 5 15 NS Smoking () 5 6 Hypertension (þ) 3 4 NS Hypertension () 7 17 Hypercholesterolemia (þ) 0 1 NS Hypercholesterolemia () 10 20 BMI (kg/m2), mean SE 21.1 2.8 19.5 2.4 NS Chemotherapy Low dose 8 17 NS Standard dose 2 4 Abbreviations: LV Z left ventricle; NS Z nonsignificant (p > 0.05); BMI Z body mass index.
The Netherlands), and a cardiac coil with five channels was used. The LVF was evaluated using cine MR imaging with 20 heart phases, a 350-mm field of view, 10-mm slice thickness, 0-mm slice gap, 192 184 matrix, 3.2-ms repetition time, 1.6-ms echo time, 55 flip angle, and balanced turbo field-echo sequence. The cine MR imaging was obtained before CCRT for all 31 patients, at a primary lesion dose of approximately 40 Gy for 27 patients, and after CCRT for 19 patients. The duration between the MR examination before CCRT and the start of CCRT was 0e11 days, and the median was 1 day. The duration between the MR examination after CCRT and the completion of CCRT was 0e12 days, and the median was 3 days. The exact radiation doses to the primary lesion at the MR examination performed at approximately
Fig. 1. Scheme of the treatments. CCRT Z concurrent chemoradiotherapy; MRI Z magnetic resonance imaging.
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40 Gy and after CCRT were distributed from 34.2 to 43.4 Gy (median, 41.4 Gy) and from 60.0 to 71.4 Gy (median, 65.4 Gy), respectively. (Some patients received MR examination either at approximately 40 Gy or after CCRT.)
Data acquisition and analysis Patient characteristics were compared as follows: age and body mass index were compared between low and high LV-dose groups using a t test, and other categoric data were compared using a c2 test. Probability (p) values of <0.05 were considered statistically significant. The LVF analysis was performed with View Forum (Philips Medical Systems) and by M.Y. and K.N. in consensus (M.Y. has 8 years of experience in cardiac imaging, and K.N. has 15 years of experience in MR imaging). Both were blinded to the CCRT method used for each patient. Several parameters related to LVF (end-diastolic volume index [LV-EDVI], end-systolic volume index [LVESVI], stroke volume index [LV-STVI], ejection fraction [LV-EF], cardiac output index [COI], heart rate [HR], and LV wall motion [LV-WM] and LV wall thickening [LV-WT] at the mid-LV portion [segments 7e12 according to the American Heart Association]) were measured and compared between before CCRT and at approximately 40 Gy or after CCRT using a Wilcoxon matchedpairs single rank test. The parameter ratios of LV-EF, LV-EDVI, LVESVI, LV-STVI, HR, COI, LV-WM, LV-WT, and body weight at approximately 40 Gy (i.e., the LV-EF, LV-EDVI, LV-ESVI, LVSTVI, HR, COI, LV-WM, LV-WT, and body weight at approximately 40 Gy divided by those before CCRT) and those after CCRT (LV-EF, LV-EDVI, LV-ESVI, LV-STVI, HR, COI, LV-WM, LV-WT, and body weight after CCRT divided by those before CCRT) were compared between the low and high LV-dose groups using a t test. A p value <0.05 was considered statistically significant. Data were expressed as the mean SE unless otherwise specified. To minimize the effects of height and body weight, LV-EDVI, LV-ESVI, LVSTVI, and COI (divided by body surface area) were used.
Results Patient classification according to LV dose The low LV-dose group included 10 patients and consisted of cervical and upper thoracic cancers. The mean LV dose was <0.6 Gy (mean, 0.37 Gy) at MR examination at approximately 40 Gy and <0.5 Gy (mean, 0.33 Gy) at MR examination after CCRT. The constitution of the patients undergoing cine MR imaging differed between the MR examinations at approximately 40 Gy and that after CCRT; therefore, the mean LV dose at MR examination at approximately 40 Gy was greater than that at MR examination after CCRT. The high LV-dose group included 21 patients and consisted of mid- and lower thoracic cancers, including 1 case of cervical cancer with extended lymph node metastasis. The mean LV dose was distributed from 3.6 to 29.4 Gy (mean, 15.5 Gy; median, 15.6 Gy) at MR examination at approximately 40 Gy and from 4.6 to 41.2 Gy (mean, 18.1 Gy; median, 16.3 Gy) at MR examination after CCRT. There were no significant differences with respect to age, gender, disease stage, cardiac risk factors, or chemotherapy method between patients receiving low and high LV doses, but the primary lesion location did differ significantly between the two dose groups. The
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Fig. 2. Representative dose distributions of cases in the low left ventricle (LV)-dose (a, b) and high LV-dose (c, d, e) group. Coronal (a) and axial (b) views of dose distribution in a case with cervical esophageal cancer. Left ventricle receives no direct radiation. Coronal (c), axial (d), and short LVaxis (e) views of dose distribution in a case with mid-thoracic esophageal cancer. A summation of the anteroposterior and parallel opposed oblique fields is shown. Numbers indicate the cardiac segments according to the American Heart Association classification (e). classification of patient characteristics according to LV dose is summarized in Table 1.
Comparison of parameters related to LVF between before CCRT and at approximately 40 Gy or after CCRT In the low LV-dose group, the LV-EF decreased significantly (p < 0.05) both at approximately 40 Gy (59.8% 2.56%) and after
CCRT (60.6% 3.89%) compared with before CCRT (62.7% 2.98%). No other parameters showed significant change. In the high LV-dose group, the LV-EF, LV-EDVI, and LV-STVI decreased significantly (p < 0.05) after CCRT compared with before CCRT. The HR increased significantly (p < 0.01) both at approximately 40 Gy and after CCRT compared with before CCRT. The LV-WM of segments 8, 9, and 10 decreased significantly (p < 0.05) both at approximately 40 Gy and after CCRT compared with before CCRT. No other parameters showed significant change. The data are summarized in Table 2.
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Change of left ventricular function in the high LV-dose group MR examination Parameter
LV-EF (%) LV-EDVI (mL/m2) LV-STVI (mL/m2) HR (beats/min) LV-WM (mm) in segment 8 LV-WM (mm) in segment 9 LV-WM (mm) in segment 10
Before CCRT 56.9 69.1 38.6 66.8 6.64 6.88 9.22
1.79 2.93 1.56 3.05 0.54 0.45 0.48
40 Gy 55.0 64.7 35.2 72.4 4.78 5.04 8.08
1.42 2.49 1.11 4.04y 0.43y 0.38y 0.34*
After CCRT 52.8 57.0 29.9 85.4 4.79 5.27 8.19
1.15* 3.23y 1.60y 3.75y 0.50* 0.47y 0.56*
Abbreviations: LV Z left ventricle; MR Z magnetic resonance; CCRT Z concurrent chemoradiotherapy; EF Z ejection fraction; EDVI Z enddiastolic volume index; STVI Z stroke volume index; HR Z heart rate; WM Z wall motion. * p < 0.05 vs. before CCRT. y p < 0.01 vs. before CCRT.
Comparison of parameter ratios related to LVF between the low and high LV-dose groups Significant differences (p < 0.05) in the parameter ratios between the low and high LV-dose groups were observed only in the values calculated after CCRT for LV-EDVI ratio, LV-STVI ratio, HR ratio, and LV-WM ratio of segment 9. No other parameters, including LV-EF ratio and body weight ratio, showed significance either at approximately 40 Gy or after CCRT. The results are summarized in Fig. 3.
Discussion The results of this study indicate that LVF, both systolic and diastolic, is impaired from an early treatment stage in patients who received cisplatin and 5-fluorouracilebased CCRT for esophageal cancer. The cardiac toxicity of CCRT for esophageal cancer has been considered as one of the late toxicities (3, 8, 9); however, the results of this study reveal that parameters related to LVF decrease significantly immediately after CCRT compared with those before CCRT. To our knowledge, this is the first report to detect acute cardiac dysfunction, that is a reduction in LV-EF, LV-EDVI, LV-STVI, and LV-WM and an increase in HR, using cine MR imaging in patients who received CCRT for esophageal cancer. As for LV-EF, a significant reduction has also been reported in patients who received platinum-based chemoradiotherapy for esophageal cancer after treatment, according to multigated acquisition scanning (10, 11). Cisplatin and 5-fluorouracilebased chemotherapy impairs systolic LVF. Systolic dysfunction detected as a reduction in LV-EF was observed both in the low LV-dose and high LV-dose groups in the present study. This suggests that the decrease in LV-EF may happen irrespective of the LV radiation dose. The fact that the ratios of LV-EF after CCRT (i.e., the LV-EF after CCRT divided by the LV-EF before CCRT) showed no significant difference between the low and high LV-dose groups supports this interpretation (Fig. 3). The fact that 5-fluorouracil has been reported to induce ischemic syndrome, arrhythmia, and cardiomyopathy (12, 13) is not discrepant with our results. Late cardiovascular complications by cisplatin have also been reported (14). Platinum-based therapies are also known to increase the risk of thrombus formation (15e17).
Direct radiation to LV might impair diastolic LVF dominantly. In the high LV-dose group, the LV-EDVI and LV-STVI decreased significantly after CCRT (Table 2), and the LV-ESVI showed no significant change. Further, the impairment of LV-WM was detected both at approximately 40 Gy and after CCRT only at segments 8, 9, and 10 (Table 2), where the radiation dose is higher than at the other segments (Fig. 2). These results suggest that direct radiation to LV might predominantly impair diastolic function through a restriction of wall motion in the radiated areas. The result that a significant difference was observed in the ratio of LV-EDVI, LV-STVI, and LV-WM in segment 9 after CCRT between the low and high LV-dose groups supports this interpretation (Fig. 3). The fact that the ratio of LV-EF after CCRT showed no significant difference between the low and high LV-dose groups also supports this interpretation (Fig. 3). Radiation-induced direct myocardial damage, that is, a significant elevation in troponin I and brain natriuretic peptide during radiotherapy for lung and breast cancer, has been reported (18). In the present study, T2weighted images with fat saturation were obtained in some cases as to detect edematous or fibrotic change of LV; however, no signal increase or decrease in the irradiated areas compared with the nonirradiated areas was observed visually (data not shown). We suspected that a difference in the degree of dehydration related to CCRT between the low and high LV-dose groups may have affected the results, with respect to the decrease in LV-EDVI and increase in HR, and we therefore compared the ratio of body weight between these two groups. However, no significant difference was observed. We consider that a difference in the degree of dehydration related to CCRT does not affect the results. Late diastolic dysfunction and its association with stress-induced ischemia and a worse prognosis have been reported in patients who received mediastinal radiation of >35 Gy for Hodgkin’s disease (19). On the other hand, in breast cancer, systolic LV dysfunction, a regional strain and strain rate reductions, immediately after adjuvant radiotherapy has been reported in a study assessing LVF using cardiac ultrasonography (20). The difference in the extent and location of LV that receive radiation may contribute to the difference in results between breast and esophageal cancer. The LV area included in the radiation field is usually restricted to the apex in only left-sided breast cancer. We also consider that the lack of change in COI in the high LV-dose group either at approximately 40 Gy or after CCRT was probably due to a compensation for the decrease in LV-STVI by the elevation of HR. The fact that LV-STVI and HR showed the opposite
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Fig. 3. Comparison of parameter ratios (after concurrent chemoradiotherapy [CCRT]/before CCRT) between low left ventricle (LV)-dose and high LV-dose groups. Left ventricle ejection fraction (LV-EF) ratio (a), LV end-diastolic volume index (LV-EDVI) ratio (b), LV stroke volume index (LV-STVI) ratio (c), heart rate (HR) ratio (d), and LV wall motion (LV-WM) ratio of segment 9 (e) are shown. directional changes after CCRT supports this interpretation (Table 2 and Fig. 3). The results of this study are limited in that the total number of patients is small. A more comprehensive study with a larger number of patients and detailed evaluation on cardiac function, including diastolic LVF, will be needed to reach a definitive conclusion. Further, a study with longer observation time may also be needed to determine whether the acute cardiac impairment observed in this study continues to correlate with late cardiac toxicities. In conclusion, cisplatin and 5-fluorouracilebased CCRT for esophageal cancer impairs LVF from an early treatment stage, and this impairment is prominent in the high LV-dose group.
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16. Feldman DR, Bosl GJ, Sheinfeld J, et al. Medical treatment of advanced testicular cancer. JAMA 2008;299:672e684. 17. Torrisi JM, Schwartz LH, Gollub MJ, et al. CT findings of chemotherapy-induced toxicity: What radiologists need to know about the clinical and radiologic manifestations of chemotherapy toxicity. Radiology 2011;258:41e56. 18. Nellessen U, Zingel M, Hecker H, et al. Effects of radiation therapy on myocardial cell integrity and pump function: Which role for cardiac biomarkers? Chemotherapy 2010;56:147e152. 19. Heidenreich PA, Hancock SL, Vagelos RH, et al. Diastolic dysfunction after mediastinal irradiation. Am Heart J 2005;150: 977e982. 20. Erven K, Jurcut R, Weltens C, et al. Acute radiation effects on cardiac function detected by strain rate imaging in breast cancer patients. Int J Radiat Oncol Biol Phys 2011;79:1444e1451.